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Introduction to pharmacokinetics
Lecture Details Wayne Hodgson; Week 6 MED1011; Pharmacology Lecture Content Properties affecting absorption and distribution are pharmaceutical form (tablet, capsule, ointment etc), dispersion and dissolution, lipid solubility/ionisation, molecular shape and size. Movement across membranes can be passive through lipid membranes, passive diffusion through aqueous channels, carrier mediated transport (facilitated diffusion, active tranport). Lipid solubility is low if the drug is ionised. Some drugs are weak acids or bases and exist in ionised and unionised forms, ratio depends on pH, unionised is able to cross membranes. Percentage ionised depends on pKa, which is the pH where 50% is ionised/unionised. Larger bulky molecules diffuse slower than small ones, are less likely to cross biological membranes, lipid solubility has more impact on diffusion. Oral bioavailability is a measure of how much drug is absorbed into the systemic circulation after oral compared to IV infusion; dependant on pharmaceutical formation, absorption across gut, first pass liver metabolism. Speed of oral absorption depends on rate of dispersion/dissolution of dosage form, drug properties, gastric emptying time, gastric pH, intestinal surface area and transit time. May be desirable to delay absorption to produce local effect or prolong systemic action. Ion trapping is when ions are less likely to cross biological membranes when they are charged, weak electrolytes will accumulate where they are most highly ionised (for weak acids such as aspirin ionisation is greatest at alkaline pH eg urine). Distribution of drugs is affected by plasma protein binding, penetration into fluid and binding to extravascular sites including tissues. Plasma protein binding removes drug from activity, some drugs compete for binding sites on albumin (anticoagulants, steroids, NSAIDs, sulphonylureas). Volume of distribution is theoretical, it is the volume into which all drug would be distributed if its concentration everywhere was the same as in plasma; is high if there is extensive extravascular binding and low if it is confined to plasma or extensively bound to plasma proteins. : >5L drug is contained in vascular compartment, <15L drug is restricted to ECF, <15L drug distributed through total body water : Vd = dose / [plasma] Therapeutic index relates dose of drug producing adverse effects to drug producing desired effect, can be high (desirable) or low (makes dose critical). Elimination of drugs can be from tissue redistribution via circulation (effects of IV sedative decrease as drug is redistributed), biotransformation, excretion. Metabolism is mainly in the liver, makes lipid soluble drugs more water soluble to allow excretion, depends on many types of enzymes, first pass through the liver may reduce amount of drug into general circulation. Most drug biotransformations are catalysed by liver enzymes, as drug concentration increases enzymes become saturated. Kinetics of removal then change from first order (rate of reaction proportional to concentration) to zero order (rate of reaction is constant and independent of drug concentration) which look like curves for first order that plateau and lines for second order. Alcohol is removed by zero order kinetics. Administration of some drugs activates metabolising enzymes which can interfere with other products metabolised by the same enzymes. Metabolism has phase I (functionalisation) chemical reaction which produces a more water-soluble metabolite, and phase II reactions which are conjugation, drug or metabolite combined with an endogenous molecule which produces a more water-soluble metabolite. Phase I reactions may produce a more active group which allows a phase II reaction. Can also produce toxic and active conversions of prodrugs/conversions. Microsomal enzymes in the endoplasmic reticulum of liver, kidney, intestine and has about 74 gene families. There are many isoforms of microsomal enzymes and competition between drugs can occur. Phase I reactions not involving microsomal enzymes are alcohol (alcohol dehydrogenase), monoamine oxidases, hydrolytic reactions. Kidneys are major site of water soluble excretion, lungs can remove gases/volatile liquids, gut (some removed by bile/faeces), sweat, saliva, mucous and tears can excrete small amounts of drugs. Readings Rang and Dale (6th); 98-112, 113-127=